The US Food and Drug Administration proposed a new 'Plausible Mechanism' framework to accelerate personalized genomic therapies for ultra‑rare diseases where traditional randomized controlled trials are infeasible. The draft guidance aims to allow mechanistically targeted, individualized interventions to proceed on an expedited regulatory pathway provided sponsors submit robust evidence of target engagement and biological effect. The proposal frames genome editing and RNA medicines as candidates for tailored review but leaves industry seeking clarification on evidentiary standards, post‑approval data requirements, and how regulators will balance flexibility with safety. Stakeholders have urged rapid engagement to refine definitions and avoid ambiguity that could delay developer plans. Regulatory clarity and operational guidance from FDA will shape investment and trial design for bespoke therapies addressing ultra‑rare genetic disorders.